Download Propionic Acidemia Screening in the Amish and Mennonite

Propionic Acidemia Screening in the
Amish and Mennonite Populations
Zineb Ammous, MD
Clinical Geneticist
Medical Director, The Community Health Clinic
“Be not conformed to this world….”
Romans 12:2
Amish populations by state
Topeka Indiana
LaGrange/ Elkhart Counties
Indiana Plain Church Population
over 46,000
• Community supported clinic providing low cost, local care for patients
with genetic disorders in the Plain Population of Northern Indiana.
• Operations began in Sep 2013
• Now serving over 500 patients from 8 states with more than 100
different disorders.
• Newborn screening follow-up for 11 northeastern Indiana counties
since July 2013
• Full Service Dental Clinic
• Offering Ancillary services to limit required travel
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Medical Home/Care Coordination
Dietary services
Audiology, Speech Therapy, Occupational Therapy
WES and Medical food assistance funds
Host the Plain Church Group Ministry
Background
• Propionic Acidemia (PA) is found in Amish and Mennonite (“Plain”)
populations throughout North America.
• The founder mutation PCCB c.1606A>G has significant residual
enzyme activity making acute neonatal presentations rare and
leading to these cases often being described as phenotypically
benign and not requiring medical intervention.
• However episodic devastating ketoacidotic crises typically occur at
times of illness or increased catabolism and can be associated with
metabolic strokes resulting in movement disorders and other
neurological complications as seen in some patients followed by
two of the clinics providing care for Plain children with PA: the
Community Health Clinic (CHC) in Indiana and the Clinic for Special
Children (CSC) in Pennsylvania.
Background
• A cohort study performed by the CSC showed that at least 25% of
the patients develop cardiac complications and heart failure, often
following a minor illness without a metabolic crisis.
• Propionyl-carnitine levels are >1000 times higher in the
myocardium than the blood. Amino acids & odd chain fatty acids
transported into myocardium & oxidized.
• Although dilated cardiomyopathy and congestive heart failure can
be reversed with treatment in some patients, others may still suffer
from metabolic crises, irreversible heart failure, and sudden cardiac
death when untreated.
[D. Holmes Morton. Cardiomyopathy is common in the propionic acidemia Amish-Mennonite variant
PCCBc.1606A>G and can be prevented & reversed by metabolic therapy. Society of Inherited Disorders of
Metabolism, Asilomar California March 2014 ]
Experience at the CSC
[Propionogenesis in Brain: Implications for Management Disorders of Propionate Metabolism.
Society for the Study of Inborn Errors of Metabolism, Lyon, France September 2015]
Clinic observations of 69 Amish and Mennonite children & adults,
homozygous for PCCB C.1606A>G, p.Asn536Asp:
• Non-treatment group: historical controls, included 51 patients on selfselected low protein diets.
• Treatment Group included 5 neonates managed over 4 years and 13
children & adults (median age 11 yrs, range 4-32 yrs)
 Treatment = Dietary protein intake of 1 g/kg/day (range 0.3 - 1.7), carnitine
25-100 mg/kg/day, PA-Amino Acid Supplements 0.5-1 g/kg-d, & Citrate 0.5-1
mEq/kg-d.
 Monitoring: Growth, exams, CBCs, chemistries, plasma amino acids &
calculated LAT1-transport, urine methylcitrate/creatinine ratios, urine
citrate/methylcitrate ratios, LV-ejection & shortening fractions, and QTc by
EKG.
OUTCOMES IN UNTREATED PATIENTS
• High mortality – 9/51 (18%)
• 1 heart transplant
• 2/3 of the cardiac deaths were from dilated cardiomyopathy; 1/3
from sudden cardiac death, probably associated with long QTc. Age
at death 2-24 yrs.
• Neurological outcomes were also poor: seizures associated with
illness were common. In some cases recurrent seizures evolved into
intractable epilepsy, dystonia arising from internal globus pallidus
degeneration, and poor school performance associated with
Attention Deficit Hyperactivity Disorder.
• Cardiomyopathy, lethal arrhythmias, seizures, encephalopathy,
metabolic strokes and cognitive decline occurred at all ages, with or
without keto-acidotic crisis.
• Hyperammonemia was not reported.
OUTCOMES IN TREATED PATIENTS
• Cardiomyopathy improved or stabilized.
• There were no cardiac deaths or heart
transplants.
• Seizures were rare, no patient developed
epilepsy.
• Growth & exams were normal.
• Children attended school in normal classes
and performances were similar to siblings &
parents. Formal IQ-testing was not done.
PCCB C.1606A>G IS NOT A BENIGN VARIANT OF
PROPIONIC ACIDEMIA!!!
Treatment improves cardiac & neurological
outcomes.
Preventing Newborn Screening Misses
Algorithm proposed by Dr. Greg Rice - University of Wisconsin
Screening for Propionic Acidemia – Amish variant
• Propionyl-carnitine levels in the blood are typically low – often falling
below screening MS/MS cut-off values.
• The variant was not recognized in the Amish & Mennonite populations
in Pennsylvania before MS/MS based NBS started in 1994
• The ratio of C3/C16 carnitine may be the most sensitive and specific
value for detecting propionic acidemia.
• If the cut-off is C3<5umol/L, 7 of 47 cases (15%) would be False
Negatives.
• If the cut-off is C3/C16 carnitine ratio < 2.2, all samples would have
been positive, none of the 47 would have been reported as False
Negative.
 If the C3/C16 ratio is abnormal then do targeted mutation analysis for
PCCB c1606 A>G.
(Dr. D. Holmes Morton – SIMD 2014)
Screening for Propionic Acidemia – Amish variant
Experience at the CSC
Missed case in IN in 2013
• A two-week old Amish female presented to the CHC for counseling after
receiving DNA results confirming homozygosity for PCCB c.1606A>G.
• Initial NBS reported at 2 weeks of life with mild elevation of Tyrosine
• Repeat NBS was reported as normal.
• The C3 level was 3.60umol/L and 2.138umol/L respectively.
• The idea of a high C3 cutoff as a reason for this false negative was
considered but lowering it enough to detect all cases with the
Amish/Mennonite variant would significantly increase the number of false
positives in the general population.
• The utility of certain acylcarnitine ratios as secondary screening analytes
was questioned:
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C3/C2: normal on initial screen (0.15), elevated on repeat (0.25)
C3/C0: elevated on initial screen (0.19), normal normal on repeat (0.15)
C3/C16: normal on initial screen (1.11), elevated on repeat (3.01)
 These ratios, therefore, are not consistently diagnostic.
What about the others?
• In addition to this confirmed missed case, we
have received reports from community
members of several cases of sudden cardiac
death in young Amish adults with known family
history of PA who were never diagnosed or
treated. Their postmortem examination
revealed dilated cardiomyopathy and signs of
heart failure.
Conclusions
• These observations and cases suggest that
supplemental NBS for unique populations may be
merited. Targeted mutation analysis with realtime PCR for the Plain community would enhance
specificity for PA and other potentially lifethreatening disorders with known founder
mutations.
• Other conditions to be considered: SCID - ADA
deficiency and RAG1 in the Old Order Amish and
IL7R in the Mennonites.
Summary
• Propionic Acidemia due to homozygosity for PCCB
C.1606A>G is one of the most common inherited
metabolic disorders in the Plain populations in the
United States.
• PCCB C.1606A>G is not a benign variant
• Identification through NBS and early treatment is
crucial in the prevention of neurological and cardiac
morbidities and mortality.
• Due to low accumulations of propionyl-carnitine, cases
can be missed by MS/MS screening.
• Supplemental NBS for such unique populations using
targeted mutation analysis with real-time PCR should
be considered and carefully implemented.
Acknowledgments
• Christopher Roberson, JD, MPH, director of the Das
KIND Program
• D. Holmes Morton, MD, founder of the Clinic for
Special Children.
• CHC and CSC PA Patients and their families